US8383673B2 - Nitridoosmium(VI) complexes for treatment of cancer - Google Patents
Nitridoosmium(VI) complexes for treatment of cancer Download PDFInfo
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- US8383673B2 US8383673B2 US12/727,732 US72773210A US8383673B2 US 8383673 B2 US8383673 B2 US 8383673B2 US 72773210 A US72773210 A US 72773210A US 8383673 B2 US8383673 B2 US 8383673B2
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- chlorine
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/002—Osmium compounds
- C07F15/0026—Osmium compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to nitridoosmium complexes that are useful as cancer treatments.
- Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs.
- the field of metal-based anticancer drugs was initiated by the platinum compound cisplatin, one of the leading agents in clinical use. Its importance is reflected by the fact that it is estimated that 50-70% of cancer patients are treated with metal-based drugs.
- cisplatin has some undesirable side effects and toxicities and, in addition, many solid tumors that initially respond to platinum-based therapy become resistant, and disease recurs. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action.
- Ruthenium compounds have been shown to have cytotoxic activity against human cancer cells. Some ruthenium complexes which have been shown to exhibit antitumor activity have been selected for clinical development as anticancer agents, specifically (H 2 im)[trans-RuCl 4 (imidazole)(DMSO)] (NAMI-A) and (H 2 ind)[trans-RuCl 4 (indazole) 2 ] (KP1019). These compounds also seem to have anti-metastatic activity.
- nitridoosmium(VI) complexes are known.
- the present invention provides a novel class of nitridoosmium complexes and methods of using them for their tumor inhibiting activity. These are potentially useful for the treatment of cancer.
- the invention relates to a method of treating a proliferative disorder comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one Os(VI) complex according to Formula I
- At least one of W, X, Y and Z is a negatively charged electron donor ligand, and at least one of A, W, X, Y and Z is an optionally substituted heterocycle, other than imidazole or benzimidazole.
- the invention relates to a compound of Formula II
- A′, W′, X′, Y′ and Z′ are selected from electron donor ligands
- At least one of W′, X′, Y′ and Z′ is halogen, water or hydroxyl. Additionally, if none of A′, W′, X′, Y′ and Z′ forms a multidentate ligand, then at least one of A′, W′, X′, Y′ and Z′ is optionally substituted pyrazole or indazole. Also, a multidentate ligand formed by any of A′, W′, X′, Y′ and Z′ is selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate.
- the invention in another aspect, relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of Formula I and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises at least one compound of Formula I and at least one additional anti-cancer agent.
- the invention in another aspect, relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of Formula II and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises at least one compound of Formula II and at least one additional anti-cancer agent.
- FIG. 1 depicts the results of the testing of a compound of the invention with and without cisplatin in the Microculture Tetrazolium Test (MTT) assay.
- MTT Microculture Tetrazolium Test
- Nitridoosmium compounds of the invention have been found to exhibit cytotoxic activity against several different types of cancer cell lines and can therefore be expected to show anticancer activity.
- Compounds of the invention may be effective in treating and/or preventing tumors caused by cells that are resistant to other cytotoxic drugs, such as cis-platin, for example.
- An electron donor ligand refers to a ligand attached to the transition metal via a coordinative bond.
- the term negatively charged ligand is defined as a ligand in which the coordinating atom itself is negatively charged so that on coordination to a positively charged metal, the negative charge is neutralized.
- a halide such as chloride or fluoride meets the present definition while a pyridine ligand bearing a negatively charged sulfonate group does not if the sulfonate group does not participate in coordination.
- Examples of negatively charged ligands include, but are not limited to, —F, —Cl, —Br, —I, —CN, —SCN, —OH, alkoxy, alkylthio and phenoxide.
- Examples of electron donor ligands include, but are not limited to, imine, water, halogen, amine, diamine, triamine, ammonia, alkyl, cyano, nitro, SCN, NH 2 , NH 3 , hydroxyl, alkoxy, phenoxy, oxalate, alcohol, alkylthio, thiol, thiolate, phosphite, ⁇ -diketone, alkylthio, phosphine, alkylnitrile, nitrite, nitrate, isocyanide, isocyanate, azide, a divalent sulfur-containing radical and optionally substituted heterocycle.
- the suffix “dentate” refers to the number of linkages formed by a ligand with a central metal atom in a coordination complex. If one atom of the ligand binds to the metal atom, the ligand is monodentate. If two atoms of the ligand bind to the metal atom, the ligand is bidentate. If three atoms of the ligand bind to the metal atom, the ligand is tridentate. If four atoms of the ligand bind to the metal atom, the ligand is tetradentate (and so on).
- structure 1 is a bidentate ligand (A and W are the same ligand, linked in two places to Os), and structure 2 below is a tetradentate ligand (Y, X, Z and W are all the same ligand, linked in four places to Os):
- a and W are part of the same single ligand, but are linked to the osmium atom in two places.
- the following compound could be a tridentate ligand, with links to the osmium at the nitrogen and at the two —OH groups:
- Y, X, Z and W are all part of the same ligand, but are linked to the osmium atom in four places.
- a ligand is an amide of picolinic acid and a diamine, such as the N,N′-1,2-diaminocyclohexane-diylbis(2-pyridinecarboxamide) shown below:
- Suitable monodentate ligands may be represented by alkyl, cyano, nitro, SCN, NH 2 , NH 3 , phosphine, alkylnitrile, nitrite, nitrate, isocyanide, isocyanate, azide, alkoxy, phenoxy, alcohol, thiol, thiolate, phosphite, and optionally substituted heterocycle.
- Examples of other suitable monodentate ligands include, but are not limited to, alkylamine, dialkylamine, trialkylamine, diamine, imine (such as, but not limited to, a Schiff base), oxalate, glycol, alkylthio or heterocyclic compounds.
- a heterocycle may be substituted with one or more instances of lower alkyl, lower alkoxy, hydroxyl, alcohol, halogen, nitro, halo(lower)alkyl, NH 2 or cyano.
- a bidentate ligand in some instances, is an imine. In some cases, the imine is a Schiff base. In other instances, the bidentate ligand is a diamine. In some cases, the diamine may be ethylenediamine or propylenediamine. In yet other instances, the bidentate ligand is 8-hydroxyquinoline. In still other instances, the bidentate ligand is a glycol. In some cases, the glycol may be ethylene glycol or propylene glycol. In further instances, the bidentate ligand is picolinic acid. In other instances, the bidentate ligand is 2-hydroxypyridine. In yet other instances, the bidentate ligand is pyridine-2-thiol. In still other instances, the bidentate ligand is a ⁇ -diketone. In some cases, the ⁇ -diketone is acetylacetonate. In further instances, the bidentate ligand is oxalate.
- a tridentate ligand is, in some aspects of the invention, an imine.
- the imine is a Schiff base.
- the Schiff base may be N-salicylidene-2-aminophenol dianions.
- the tridentate ligand is a triamine.
- the tridentate ligand is tris(1-pyrazolyl)borohydride anion or tris(1-pyrazolyl)methane.
- the tridentate ligand is 2,2′:6′,2′′-terpyridine or 2,2′:6′,2′′-terpyrimidine.
- the tridentate ligand is a dicarboxylic acid of a nitrogen-containing heterocycle, wherein the carboxylic acids are adjacent to the nitrogen (for instance, pyridine-2,6-dicarboxylic acid).
- the formulae shown below may be mono-, bi- or tridentate ligands:
- R 1 and R 2 each represent one, two or three substituents and are each independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, nitro, NH 2 and cyano. In some of these substituents, R 2 is positioned para to the oxygen.
- a tetradentate ligand is, in some instances of the invention, an amide of picolinic acid and a diamine, for instance, N,N′-1,2-diaminocyclohexane-diylbis(2-pyridinecarboxamide).
- the tetradentate ligand may be an imine.
- the imine is a Schiff base.
- the tetradentate ligand may be the Schiff base of salicaldehyde and a diamine, such as those shown below:
- R 1 can represent substituents such as (but not limited to) hydrogen, lower alkyl or halogen
- R 2 can be substituents such as (but not limited to) hydrogen, lower alkyl, halogen, nitro, or lower alkoxy.
- the invention is method of treating a proliferative disorder comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one complex according to Formula I
- n is a negative charge represented by ⁇ 3, ⁇ 2, or ⁇ 1. In other aspects of the invention, n is neutral, represented by 0. In still other aspects of the invention, n is a positive charge represented by +1, +2 or +3.
- A, W, X, Y and Z are each independently halogen, water or hydroxyl and the remaining two of A, W, X, Y and Z are each monodentate ligands.
- n is ⁇ 2, ⁇ 1 or 0.
- X, Y and Z are each independently chlorine
- W is chlorine, pyrazole or indazole
- A is a pyrazole.
- A is an indazole.
- the pyrazole and/or indazole is substituted with one or more instances of lower alkyl, lower alkoxy, hydroxyl, alcohol, halogen, nitro, halo(lower)alkyl, NH 2 or cyano.
- An illustrative compound of this subgenus is shown below:
- three of A, W, X, Y and Z are each independently halogen, water or hydroxyl and the remaining two of A, W, X, Y and Z together form a bidentate ligand.
- X, Y and Z are each independently chlorine, and A and W together form a bidentate ligand selected from imine, a diamine, 8-hydroxyquinoline, a glycol, picolinic acid, 2-hydroxypyridine, pyridine-2-thiol, acetylacetonate and oxalate.
- two of A, W, X, Y and Z are each independently halogen, water or hydroxyl.
- n is +1, 0, ⁇ 1 or ⁇ 2.
- the remaining three of A, W, X, Y and Z each are monodentate ligands.
- one of the remaining A, W, X, Y and Z is a monodentate ligand, and the remaining two together form a bidentate ligand.
- the remaining three of A, W, X, Y and Z together form a tridentate ligand, such as the representative example shown below:
- one of A, W, X, Y and Z is halogen, water or hydroxyl.
- n is +3, +2, +1, 0, ⁇ 1 or ⁇ 2.
- the remaining four of A, W, X, Y and Z each are monodentate ligands.
- one of the remaining A, W, X, Y and Z is a monodentate ligand, and the remaining three together form a tridentate ligand.
- two of the remaining A, W, X, Y and Z each are monodentate ligands, and the remaining two together form a bidentate ligand.
- n 0, ⁇ 1 or ⁇ 2
- X, Y and Z are each independently chlorine.
- A is selected from optionally substituted pyrazole and indazole and W is selected from chlorine and optionally substituted pyrazole or indazole.
- a and W together form a bidentate ligand selected from imine, a diamine, 8-hydroxyquinoline, a glycol, picolinic acid, 2-hydroxypyridine, pyridine-2-thiol, acetylacetonate and oxalate.
- the bidentate ligand is selected from a Schiff base, ethylenediamine, propylenediamine, ethylene glycol, propylene glycol, 8-hydroxyquinoline, picolinic acid, acetylacetonate and oxalate.
- the ligand is selected from Formula IIIa and IIIb:
- R 1 and R 2 are each independently selected from hydrogen, chlorine, bromine, methyl, NH 2 , methoxy, cyano and nitro, and R 2 is positioned para to the oxygen.
- n is +1, 0, ⁇ 1 or ⁇ 2; W is chlorine; Z is water or chlorine; and A, X and Y together form a tridentate ligand selected from an imine, triamine, tris(1-pyrazolyl)borohydride anion, tris(1-pyrazolyl)methane, 2,2′:6′,2′′-terpyridine, 2,2′:6′,2′′-terpyrimidine and a dicarboxylic acid of a nitrogen-containing heterocycle, wherein the carboxylic acids are adjacent to the nitrogen.
- the ligand is selected from Formula IIIa and IIIb:
- R 1 and R 2 are each independently selected from hydrogen, chlorine, bromine, methyl, NH 2 , methoxy, cyano and nitro, and R 2 is positioned para to the oxygen.
- the invention relates to a compound of Formula II
- n is a negative charge represented by ⁇ 3, ⁇ 2, or ⁇ 1. In other aspects of the invention, n is neutral, represented by 0. In still other aspects of the invention, n is a positive charge represented by +1, +2 or +3.
- A′, W′, X′, Y′ and Z′ are selected from electron donor ligands.
- A′, W′, X′, Y′ and Z′ may be optionally linked to each other in any combination.
- At least one of A′, W′, X′, Y′ and Z′ must be halogen, water or hydroxyl.
- Any multidentate ligand formed by any of A′, W′, X′, Y′ and Z′ is selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate.
- A′, W′, X′, Y′ and Z′ are monodentate ligands (that is, none are linked to each other), then at least one of A′, W′, X′, Y′ and Z′ is optionally substituted pyrazole or indazole.
- A′, W′, X′, Y′ and Z′ are each independently halogen, water or hydroxyl.
- n is ⁇ 2, ⁇ 1 or 0.
- the remaining two of A′, W′, X′, Y′ and Z′ are each monodentate ligands selected from cyano, nitro, SCN, NH 2 , NH 3 , phosphine, alkylnitrile, isocyanate, alkoxy, phenoxy, thiol, thiolate, phosphite, and optionally substituted pyrazole or indazole, at least one of which is optionally substituted pyrazole or indazole.
- X′, Y′ and Z′ are each independently chlorine, W′ is chlorine, pyrazole or indazole, and A′ is a pyrazole.
- A′ is an indazole.
- the pyrazole and/or indazole is substituted with one or more instances of lower alkyl, lower alkoxy, hydroxyl, alcohol, halogen, nitro, halo(lower)alkyl, NH 2 or cyano.
- three of A′, W′, X′, Y′ and Z′ are each independently halogen, water or hydroxyl and the remaining two of A′, W′, X′, Y′ and Z′ together form a bidentate ligand selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate.
- X′, Y′ and Z′ are each independently chlorine, and A′ and W′ together form a bidentate ligand selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate.
- two of A′, W′, X′, Y′ and Z′ are each independently halogen, water or hydroxyl.
- n is ⁇ 2, ⁇ 1, 0 or +1.
- the remaining three of A′, W′, X′, Y′ and Z′ each are monodentate ligands, at least one of which is optionally substituted pyrazole or indazole.
- one of the remaining A′, W′, X′, Y′ and Z′ is a monodentate ligand, and the remaining two together form a bidentate ligand selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate.
- the remaining three of A′, W′, X′, Y′ and Z′ together form a tridentate ligand that is not 2,2′:6′,2′′-terpyridine.
- one of A′, W′, X′, Y′ and Z′ is halogen, water or hydroxyl.
- n is ⁇ 2, ⁇ 1, 0, +1, +2 or +3.
- the remaining four of A′, W′, X′, Y′ and Z′ each are monodentate ligands selected from cyano, nitro, SCN, NH 2 , NH 3 , phosphine, alkylnitrile, isocyanate, alkoxy, phenoxy, thiol, thiolate, phosphite, and optionally substituted pyrazole or indazole, at least one of which is optionally substituted pyrazole or indazole.
- one of the remaining A′, W′, X′, Y′ and Z′ is a monodentate ligand selected from cyano, nitro, SCN, NH 2 , NH 3 , phosphine, alkylnitrile, isocyanate, alkoxy, phenoxy, thiol, thiolate, phosphite, and optionally substituted pyrazole or indazole, and the remaining three together form a tridentate ligand that is not 2,2′:6′,2′′-terpyridine.
- two of the remaining A′, W′, X′, Y′ and Z′ each are monodentate ligands selected from cyano, nitro, SCN, NH 2 , NH 3 , phosphine, alkylnitrile, isocyanate, alkoxy, phenoxy, thiol, thiolate, phosphite, and optionally substituted pyrazole or indazole, and the remaining two together form a bidentate ligand.
- two of the remaining four of A′, W′, X′, Y′ and Z′ together form a bidentate ligand, and the remaining two of A′, W′, X′, Y′ and Z′ together form another bidentate ligand.
- the bidentate ligands may be an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate.
- the remaining four of A′, W′, X′, Y′ and Z′ together all form a tetradentate ligand.
- n 0, ⁇ 1 or ⁇ 2 and X′, Y′ and Z′ are each independently chlorine.
- A′ is selected from optionally substituted pyrazole and indazole and W′ is selected from chlorine and optionally substituted pyrazole or indazole.
- A′ and W′ together form a bidentate ligand selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate.
- the bidentate ligand is selected from a Schiff base, ethylenediamine, propylenediamine, ethylene glycol, propylene glycol, 8-hydroxyquinoline and oxalate.
- the ligand is selected from Formula IIIa and IIIb:
- R 1 and R 2 are each independently selected from hydrogen, chlorine, bromine, methyl, NH 2 , methoxy, cyano and nitro, and R 2 is positioned para to the oxygen.
- the ligand is selected from Formula IIIa and IIIb.
- Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl.
- Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
- Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s- and t-butyl, cyclobutyl and the like. Preferred alkyl groups are those of C 20 or below.
- Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 or more carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
- Alkenyl refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals contain from 2 to 10 or more carbon atoms, preferably from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms.
- suitable alkenyl radicals include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, alkadienes and the like.
- Alkynyl refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one triple bond. Such radicals contain from 2 to 10 or more carbon atoms, preferably from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples of suitable alkynyl radicals include propynyl, butyn-1-yl, pentyn-1-yl, butyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, heptyn-1-yl, and octyn-1-yl and the like.
- Alkoxy or alkoxyl refers to groups of from 1 to 8 or more carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower alkoxy refers to groups containing one to four carbons.
- Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S.
- the aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
- aryl and heteroaryl refer to residues in which one or more rings are aromatic, but not all need be.
- Heterocycle means a cycloalkyl or aryl carbocycle residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S.
- the nitrogen and sulfur heteroatoms may optionally be oxidized, and a nitrogen heteroatom not directly attached to an osmium atom may optionally be quaternized.
- a heterocycle may be non-aromatic or aromatic.
- heterocycles examples include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
- heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
- heterocyclyl residues additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazo
- substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
- substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refers to alkyl, aryl, cycloalkyl, heterocyclyl, heterocyclyl, etc.
- H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyloweralkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, loweralkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl [—C( ⁇ O)O-alkyl], alkoxycarbonylamino [HNC( ⁇ O)O-alkyl], carboxamido [—C( ⁇ O)NH 2 ], alkylaminocarbonyl [—C( ⁇ O)NH-alkyl], cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkyl, dial
- Oxo is also included among the substituents referred to in “optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
- 1, 2 or 3 hydrogen atoms are replaced with a specified radical.
- more than three hydrogen atoms can be replaced by fluorine; indeed, all available hydrogen atoms could be replaced by fluorine.
- a metal-containing moiety is not to be an allowed substituent.
- aryl optionally substituted with one or more substituents selected from halogen and alkyl indicates that the aryl could be substituted with, for instance (but not limited to) one chlorine; three chlorines; two chlorines and an ethyl; or one chlorine, two methyl groups and a fluorine.
- haloalkyl and “haloalkoxy” mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
- alkylcarbonyl and “alkoxycarbonyl” mean —C( ⁇ O)alkyl or —C( ⁇ O)—O-alkyl, respectively.
- halogen means fluorine, chlorine, bromine or iodine. In one embodiment, halogen may be fluorine or chlorine.
- Phosphines refer to a class of substituents containing a trivalent phosphorus atom having up to three substituents, —PR a R b R c , wherein the R groups are hydrogen, lower alkyl or phenyl. Triphenylphosphine, trimethylphosphine or triethylphosphine are common phosphines.
- An amine is any residue that contains one or more nitrogen(s), wherein the nitrogen is in the sp 3 configuration.
- Alcohol refers to a residue containing one or more —OH groups.
- An imine refers to a residue containing the structure —RR′C—N ⁇ R′′—, wherein the R groups are generally carbon or hydrogen.
- an imine is not contained within a ring, except where the ring is formed due to the metal complex.
- the —RR′C—N ⁇ R′′— found within the ring of pyridine or pyrimidine is not an imine for purposes of this invention.
- the structure shown below does contain an imine, even though rings are formed when the imine complexes with the metal atom:
- a Schiff base is a subset of imine with a formula of —RR′C ⁇ N—C— (i.e., R′′ is carbon, not hydrogen).
- Some Schiff bases of the invention include the N-salicylidene-2-aminophenol dianions (salpa) shown above or a Schiff base of salicaldehyde and a diamine, such as those shown below:
- R 1 can represent substituents such as (but not limited to) hydrogen, lower alkyl or halogen
- R 2 can be substituents such as (but not limited to) hydrogen, lower alkyl, halogen, nitro, or lower alkoxy.
- one or more of X, Y, Z, W and A and X′, Y′, Z′, W′ and A′ may be a ligand that can only be monodentate, such as halogen.
- monodentate ligands will only be linked to the osmium and will not be part of a higher denticity substituent.
- A, W, X, Y and Z may be optionally linked to each other in any combination,” if Z is a halogen or water, it will not be additionally linked any of A, W, X or Y.
- any hydrogen atoms on the moiety may or may not be present after complexing with the metal atom.
- reference to 8-hydroxyquinoline as a ligand choice is meant to indicate that, while 8-hydroxyquinoline is the stand-alone moiety, the hydrogens may not be present once the moiety is complexed with the metal atom (not all osmium bonds drawn below):
- pyrazole ligand may be drawn in either of the ways shown below:
- the total charge on the complex (n) will, however, change depending on the number of hydrogens that remain present.
- alkyl or aryl portions of any of the ligands are optionally substituted by —F, —Cl, —Br, —I, alkylamino, dialkylamino, trialkylammonium (except on aryl portions), alkoxy, alkylthio, aryl, or a reactive group.
- Any alkyl portions of the monodentate ligands generally contain 1 to 12 carbons. More typically, the alkyl portions contain 1 to 6 carbons.
- the monodentate ligands are optionally substituted heterocyclic compounds containing at least one nitrogen, oxygen, or sulfur atom.
- Suitable optionally substituted heterocyclic monodentate ligands include indazole, pyrazole, oxazole, thiazole, triazole, pyridine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridazine, pyrimidine, triazine, pyrazine, furan, thiophene, pyrrole, pyrroline, quinoline, isoquinoline, indole, indolizine, isoindole, benzofuran, benzothiophene, purine, phthalazine, quinazoline, quinoxaline, naphthyridine, phenazine, and the like, and derivatives thereof.
- a heterocycle when a heterocycle is attached to the osmium atom, it is attached at the heteroatom.
- a “reactive group” is a functional group of a molecule that is capable of reacting with another compound to couple at least a portion of that other compound to the molecule.
- Reactive groups include carboxy, activated ester, sulfonyl halide, sulfonate ester, isocyanate, isothiocyanate, epoxide, aziridine, halide, aldehyde, ketone, amine, acrylamide, thiol, acyl azide, acyl halide, hydrazine, hydroxylamine, alkyl halide, imidazole, pyridine, phenol, alkyl sulfonate, halotriazine, imido ester, maleimide, hydrazide, hydroxy, and photo-reactive azido aryl groups.
- Activated esters generally include esters of succinimidyl, benzotriazolyl, or aryl substituted by electron-withdrawing groups such as sulfo, nitro, cyano, or halo groups; or carboxylic acids activated by carbodiimides.
- the compounds of formula I or formula II may also be presented as a pharmaceutical composition.
- the present invention provides a pharmaceutical composition comprising a compound of formula I or II, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
- the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the compounds of formula I or II are, by definition, going to be present as salts.
- pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
- salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
- Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic (besylate), benzoic, boric, butyric, camphoric, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, formic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, oleic, pamoic, pantothenic, phosphoric, pivalic, polygalacturonic, salicylic, stearic, succin
- suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium cations and carboxylate, sulfonate and phosphonate anions attached to alkyl having from 1 to 20 carbon atoms.
- the compounds of the invention may be administered by a number of routes including, for example, orally, parenterally (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectally, topically (including dermal, buccal, sublingual and intraocular), nasally or via slow releasing microcarriers.
- routes including, for example, orally, parenterally (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectally, topically (including dermal, buccal, sublingual and intraocular), nasally or via slow releasing microcarriers.
- the most suitable route may depend upon the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula I or II or a pharmaceutically acceptable salt or solvate thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients.
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- suitable carriers for use in the pharmaceutical compositions of the invention include saline, sterile water, creams, ointments, solutions, gels, pastes, emulsions, lotions, oils, solid carriers and aerosols.
- Oral and parenteral sustained release drug delivery systems are well known to those skilled in the art, and general methods of achieving sustained release of orally or parenterally administered drugs are found in any standard pharmacy school textbook, for example Remington: The Science and Practice of Pharmacy . Chapter 94 of the 19th edition of Remington entitled “Sustained-Release Drug Delivery Systems” describes the more common types of oral and parenteral sustained-release dosage forms (pages 1660-1675.) The disclosure is incorporated herein by reference.
- the compounds of the invention may be administered orally or via injection at a dose from 0.001 to 2500 mg/kg per day.
- the dose range for adult humans is generally from 0.005 mg to 10 g/day.
- the specific dosage level of the compounds and compositions of the invention will depend upon a number of factors, including the biological activity of the specific compound used and the age, body weight and sex of the subject. It will be appreciated that the subject may be a human or a mammalian animal.
- the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
- the compounds and compositions of the invention can be administered alone or in combination with other compounds.
- the other compounds may have a biological activity which complements the activity of the compounds of the invention e.g., by enhancing its effect in killing tumors or by reducing any side-effects associated with the compounds of the invention.
- tumor is to be understood as referring to all forms of neoplastic cell growth, including tumors of the lung, liver, blood cells, skin, pancreas, stomach, colon, prostate, uterus, breast, lymph glands and bladder.
- treatment of a patient is intended to include prophylaxis.
- method of treating when used in connection with these disorders means amelioration, prevention or relief from the symptoms and/or effects associated with these disorders.
- the compounds of the invention may be used directly against a tumor. Alternatively or additionally, the compounds may be used to prevent or inhibit metastasis and/or to kill secondary tumors. It will be understood that the prevention or inhibition of metastasis is encompassed by the term “preventing cancer”, as used herein.
- structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and cis-trans isomeric) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and cis-trans isomeric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
- n Bu n-butyl
- nalph 1-[[(2-hydroxyphenyl)imino]methyl]-2-naphthalenol
- PBS phosphate buffered saline
- the red solid was prepared by a procedure similar to that [Os VI (N)(salpa)(OH 2 )Cl] using H 2 nalph as ligand. Yield: 63%.
- the purple-red powder was prepared by a procedure similar to that for [Os VI (N)(pyrazole) 2 Cl 3 ] using 3,5-dimethylpyrazole and 10 mL EtOH as solvent. Yield: 58%.
- ESI-MS acetone
- m/z +468, [Os VI (N)(3,5-dimethylpyazole) 2 Cl 2 + ].
- the cytotoxicity of the complexes was tested by using human cervix epitheloid carcinoma (HeLa) cell line. In this respect the following method was selected.
- DMEM Dulbecco's Modified Eagle's Medium
- Test execution Cell were harvested from culture plates by trypsinization and seeded in 100 ⁇ L aliquots in complete culture medium into 96-well microculture plates. Cell density of about 4800 cells/well was chosen in order to ensure exponential growth throughout drug exposure. Cells were allowed to settle for 24 h, followed by the addition of dilutions of the test compounds, which were dissolved in DMSO, in 100 ⁇ L/well complete culture medium ( ⁇ 1% DMSO) and incubation for 24 h (compound 1-7) or 48 h (compound 8-11). At the end of exposure, drug solutions were replaced by 100 ⁇ L/well DMEM medium with 10% MTT solution in phosphate-buffered saline (5 mg/ml PBS).
- NCI-H460 from ATCC
- nude mice SPF grade BALB/c-nu male nude mice were purchased from Medical Laboratory Animal Center, Guangdong Province) subcutaneously.
- the in vivo anti-cancer properties of Os1 (Compound 8) and Os2 (Compound 1) given by intraperitoneal injection were examined by measuring the tumor nodule size of the nude mice.
- Each nude mouse was inoculated subcutaneously with 0.2 mL of 7.5 ⁇ 10 6 cells/mL of NCI-H460 cells suspended in culture medium. Tumor nodules on nude mice were observed nine days after inoculation and injections of Os1, Os2, cyclophosphamide (positive control) and 20% PET solution 1 (negative control) were performed on that day.
- Os1, Os2, cyclophosphamide positive control
- cyclophosphamide positive control
- PET solution 1 negative control
- Os1 and Os2 were prepared by City University of Hong Kong, Hong Kong. Disposable sterile 1 ml syringe; vernier caliper (No. 01,000,101 River system, GB/T1214.2) Chengdu Measuring & Cutting Tool Co., Ltd. production; Tecniplast separately ventilated cage (Italy), ultra-clean bench.
- mice 16-18 g male BALB/c-nu nude mice were inoculated subcutaneously 0.2 mL of the NCI-H460 cell suspension (1.5 ⁇ 10 6 cells/rats). The day after inoculation (administration day 1), the nude mice were randomly divided into eight groups and were grouped as follows:
- Os1 groups (three treatment groups: 10, 3, 1 mg/kg, intraperitoneal injection)
- Os2 groups (three treatment groups: 10, 3, 1 mg/kg, intraperitoneal injection)
- mice in each group were received treatment twice a week, with a total number of eight injections. Tumor sizes were measured every 3 days. The treated mice were sacrificed at the end of the study period (30 days) with anatomical separation of tumor nodules. The tumors were weighed and photographed.
- Tumor growth inhibition rate (%) (1 ⁇ mean tumor weight of the treatment/mean tumor weight of the negative group) ⁇ 100%.
- Tumor volume longest dimension (mm) ⁇ [shortest dimension of the tumor (mm)] 2 /2. All measurements were expressed in Mean ⁇ SD, using SPSS 10.0 for statistical analysis.
- Tumor volume (Mean ⁇ SD) dose/ number of Tumor volume/mm 3 group mg ⁇ kg ⁇ 1 mice day 14 day 18 day 22 day 26 day 30 ⁇ ve — 5 405.5 ⁇ 834.70 ⁇ 1207.93 ⁇ 1952.96 ⁇ 2590.19 ⁇ 191.11 383.67 722.09 1294.35 1638.80 +ve 30 5 168.16 ⁇ 227.03 ⁇ 318.64 ⁇ 378.31 ⁇ 778.84 ⁇ 117.68 167.96* 334.09* 233.53* 574.55* Os1 low dose 1 5 288.12 ⁇ 518.99 ⁇ 801.59 ⁇ 1319.35 ⁇ 1569.69 ⁇ 87.38 241.97 422.76 748.80 557.16 Os1 medium dose 3 5 482.89 ⁇ 1043.37 ⁇ 1140.42 ⁇ 1537.35 ⁇ 2262.38 ⁇ 298.61 679.42 675.13 967.22 868.
- Compound 8 was tested in the MTT assay to determine its effects with and without cisplatin (see FIG. 1 ). Assays of cytotoxicity were conducted in 96-well, flat-bottomed microtitre plates. The supplemented culture medium (MEM, 40 ⁇ L) with HeLa cells (1 ⁇ 10 5 cells per mL) was added to the wells. Compound 8 was dissolved in the culture medium with 0.5% DMSO with concentrations ranged from 5 ⁇ M to 100 ⁇ M, and aliquots (10 ⁇ L) of the solutions were subsequently added to a set of wells containing the HeLa cells.
- MEM supplemented culture medium
- DMSO 0.5% DMSO
- cisplatin was dissolved in the culture medium in order to prepare solutions with concentrations of 0, 0.2, 2 and 6 ⁇ M. Aliquots of the cisplatin solutions (50 ⁇ L) were added to different sets of the wells containing compound 8 and the HeLa cells. Cells for control experiments were treated with supplemented media with 0.5% DMSO (100 ⁇ L). The microtitre plates were incubated at 37° C. in a humidified atmosphere of 5% CO 2 /95% air for a further 3 days.
- MTT Mosmann-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- microtitre plates were maintained in a dark, humidified chamber overnight.
- the formation of formazan was measured by using a microtitre plate reader at 550 nm and the percentages of cell survival were determined.
- the cytotoxicity was evaluated based on the percentage cell survival in a dose-dependent manner relative to the control. Table 3 below summarizes the results:
- Compound 8 is more effective than cisplatin in the MTT assay. Further, the presence of cisplatin does not provide any synergistic effect when administered with Compound 8.
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Abstract
Description
-
- A, W, X, Y and Z are selected from electron donor ligands;
- n is a negative, neutral or positive charge represented by −3, −2, −1, 0, +1, +2 or +3, respectively; and
- wherein A, W, X, Y and Z may be optionally linked to each other in any combination.
-
- n is a negative, neutral or positive charge represented by −1, −2 −3, 0, +1, +2 or +3; and
- wherein A′, W′, X′, Y′ and Z′ may be optionally linked to each other in any combination.
Note that in
Similarly, in structure 2 above, Y, X, Z and W are all part of the same ligand, but are linked to the osmium atom in four places. One example of such a ligand is an amide of picolinic acid and a diamine, such as the N,N′-1,2-diaminocyclohexane-diylbis(2-pyridinecarboxamide) shown below:
In these formulae, R1 and R2 each represent one, two or three substituents and are each independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, nitro, NH2 and cyano. In some of these substituents, R2 is positioned para to the oxygen.
In these examples, R1 can represent substituents such as (but not limited to) hydrogen, lower alkyl or halogen, and R2 can be substituents such as (but not limited to) hydrogen, lower alkyl, halogen, nitro, or lower alkoxy.
In another embodiment of this subgenus of the invention, three of A, W, X, Y and Z are each independently halogen, water or hydroxyl and the remaining two of A, W, X, Y and Z together form a bidentate ligand. In some members of this subgenus, X, Y and Z are each independently chlorine, and A and W together form a bidentate ligand selected from imine, a diamine, 8-hydroxyquinoline, a glycol, picolinic acid, 2-hydroxypyridine, pyridine-2-thiol, acetylacetonate and oxalate. One representative example is shown below:
In these cases, R1 and R2 are each independently selected from hydrogen, chlorine, bromine, methyl, NH2, methoxy, cyano and nitro, and R2 is positioned para to the oxygen.
In these cases, R1 and R2 are each independently selected from hydrogen, chlorine, bromine, methyl, NH2, methoxy, cyano and nitro, and R2 is positioned para to the oxygen.
In another aspect of this subgenus of the invention, three of A′, W′, X′, Y′ and Z′ are each independently halogen, water or hydroxyl and the remaining two of A′, W′, X′, Y′ and Z′ together form a bidentate ligand selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate. In some members of this subgenus, X′, Y′ and Z′ are each independently chlorine, and A′ and W′ together form a bidentate ligand selected from an imine, a diamine, 8-hydroxyquinoline, a glycol and oxalate. One representative example is shown below:
In these cases, R1 and R2 are each independently selected from hydrogen, chlorine, bromine, methyl, NH2, methoxy, cyano and nitro, and R2 is positioned para to the oxygen.
In these examples, R1 can represent substituents such as (but not limited to) hydrogen, lower alkyl or halogen, and R2 can be substituents such as (but not limited to) hydrogen, lower alkyl, halogen, nitro, or lower alkoxy.
The total charge on the complex (n) will, however, change depending on the number of hydrogens that remain present.
Cytotoxicity Tests:
TABLE |
Cytotoxicity of Nitridoosmium Complexes in HeLa Cell Line |
Compound (Example No.) | IC50 (μM)* | ||
1 | A | ||
2 | A | ||
3 | A | ||
4 | A | ||
5 | A | ||
6 | B | ||
7 | A | ||
8 | A | ||
9 | A | ||
10 | B | ||
11 | B | ||
*IC50 Values: A is <25 μM; B is <100 μM |
In Vitro Tests
Tumor growth inhibition rate (%)=(1−mean tumor weight of the treatment/mean tumor weight of the negative group)×100%. Tumor volume=longest dimension (mm)×[shortest dimension of the tumor (mm)]2/2. All measurements were expressed in Mean±SD, using SPSS 10.0 for statistical analysis.
TABLE 1 |
Tumor size measurement (Mean ± SD) |
number | ||||
of | dose/ | inhibition | ||
group | mice | mg · kg−1 | tumor weight (g) | rate (%) |
negative control | 5 | — | 2.3482 ± 1.0455 | — |
positive control | 5 | 30.0 | 0.6095 ± 0.5477* | 74.04 |
Os1 low dose | 5 | 1 | 1.7206 ± 0.4289 | 26.73 |
Os1 medium dose | 5 | 3 | 2.0631 ± 1.1693 | 12.14 |
Os1 high dose | 5 | 10 | 2.7711 ± 1.0732 | −18.01 |
Os2 low dose | 5 | 1 | 1.2164 ± 0.6547 | 48.20 |
Os2 medium dose | 5 | 3 | 1.3542 ± 0.5337 | 42.33 |
Os2 high dose | 5 | 10 | 2.1535 ± 1.4884 | 8.29 |
Compared with negative control: *P < 0.05 |
TABLE 2 |
Tumor volume (Mean ± SD) |
dose/ | number of | Tumor volume/mm3 |
group | mg · kg−1 | mice | day 14 | day 18 | day 22 | day 26 | day 30 |
−ve | — | 5 | 405.5 ± | 834.70 ± | 1207.93 ± | 1952.96 ± | 2590.19 ± |
191.11 | 383.67 | 722.09 | 1294.35 | 1638.80 | |||
+ve | 30 | 5 | 168.16 ± | 227.03 ± | 318.64 ± | 378.31 ± | 778.84 ± |
117.68 | 167.96* | 334.09* | 233.53* | 574.55* | |||
Os1 | 1 | 5 | 288.12 ± | 518.99 ± | 801.59 ± | 1319.35 ± | 1569.69 ± |
87.38 | 241.97 | 422.76 | 748.80 | 557.16 | |||
Os1 medium dose | 3 | 5 | 482.89 ± | 1043.37 ± | 1140.42 ± | 1537.35 ± | 2262.38 ± |
298.61 | 679.42 | 675.13 | 967.22 | 868.18 | |||
Os1 | 10 | 5 | 534.98 ± | 901.64 ± | 1422.37 ± | 2004.80 ± | 2511.59 ± |
236.90 | 313.88 | 581.23 | 717.39 | 1011.51 | |||
Os2 | 1 | 5 | 380.21 ± | 710.06 ± | 726.71 ± | 1365.02 ± | 1110.38 ± |
302.43 | 669.55 | 754.02 | 1222.89 | 541.57* | |||
Os2 medium dose | 3 | 5 | 420.80 ± | 500.45 ± | 1011.29 ± | 1032.38 ± | 1390.62 ± |
405.23 | 286.63 | 200.62 | 495.14 | 571.16 | |||
Os2 | 10 | 5 | 507.33 ± | 671.87 ± | 1342.17 ± | 1601.47 ± | 2188.17 ± |
411.74 | 449.98 | 1176.17 | 1286.31 | 1724.71 | |||
Compared with negative control group: *P < 0.05 |
MTT Assay:
TABLE 3 |
Results of MTT Assay |
Compound 8 | Cisplatin (concentration) | IC50 (in μM) |
Yes | None | 3.8 |
Yes | 0.1 | μM | 4.19 |
Yes | 1.0 | μM | 3.38 |
Yes | 3.0 | μM | 4.7 |
None | 0.5-100 | μM μM | 7.5 |
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